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. 2023 Nov 20;15(11):2643.
doi: 10.3390/pharmaceutics15112643.

Transferrin-Bearing, Zein-Based Hybrid Lipid Nanoparticles for Drug and Gene Delivery to Prostate Cancer Cells

Khadeejah Maeyouf  1 , Intouch Sakpakdeejaroen  1   2 , Sukrut Somani  1 , Jitkasem Meewan  1 , Hawraa Ali-Jerman  1 , Partha Laskar  1   3 , Margaret Mullin  4 , Graeme MacKenzie  1 , Rothwelle J Tate  1 , Christine Dufès  1
Affiliations

Transferrin-Bearing, Zein-Based Hybrid Lipid Nanoparticles for Drug and Gene Delivery to Prostate Cancer Cells

Khadeejah Maeyouf et al. Pharmaceutics. .

Abstract

Gene therapy holds great promise for treating prostate cancer unresponsive to conventional therapies. However, the lack of delivery systems that can transport therapeutic DNA and drugs while targeting tumors without harming healthy tissues presents a significant challenge. This study aimed to explore the potential of novel hybrid lipid nanoparticles, composed of biocompatible zein and conjugated to the cancer-targeting ligand transferrin. These nanoparticles were designed to entrap the anti-cancer drug docetaxel and carry plasmid DNA, with the objective of improving the delivery of therapeutic payloads to prostate cancer cells, thereby enhancing their anti-proliferative efficacy and gene expression levels. These transferrin-bearing, zein-based hybrid lipid nanoparticles efficiently entrapped docetaxel, leading to increased uptake by PC-3 and LNCaP cancer cells and significantly enhancing anti-proliferative efficacy at docetaxel concentrations exceeding 1 µg/mL. Furthermore, they demonstrated proficient DNA condensation, exceeding 80% at polymer-DNA weight ratios of 1500:1 and 2000:1. This resulted in increased gene expression across all tested cell lines, with the highest transfection levels up to 11-fold higher than those observed with controls, in LNCaP cells. These novel transferrin-bearing, zein-based hybrid lipid nanoparticles therefore exhibit promising potential as drug and gene delivery systems for prostate cancer therapy.

Keywords: cancer therapy; delivery system; prostate cancer; transferrin; tumor targeting; zein-based hybrid lipid nanoparticles.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
TEM pictures of (A) transferrin-bearing and (B) control zein-based hybrid lipid nanoparticles.
Figure 2
Figure 2
Size (A), polydispersity index (B), zeta potential (C), and drug retention (D) of Tf-bearing (■, blue) and control (●, red) zein-based hybrid lipid nanoparticles entrapping docetaxel after storage at 4 °C for 4 weeks (n = 4) (error bars smaller than symbols when not visible).
Figure 3
Figure 3
Drug release profile of docetaxel entrapped in Tf-bearing (■, black), control zein-based hybrid lipid nanoparticles (●, red), or in solution (▲, blue) in phosphate buffers at pH 5.5 (A), 6.5 (B), and 7.4 (C) over 24 h (n = 3) (error bars smaller than symbols when not visible).
Figure 4
Figure 4
Quantification of the cellular uptake of fluorescein-labelled docetaxel entrapped in Tf-bearing and control zein-based hybrid lipid nanoparticles or as solution in PC3-Luc (A), DU145 (B), and LNCaP (C) cells (a.u.: arbitrary units) (*: p < 0.05 vs. Tf-bearing zein-based hybrid lipid nanoparticles). Results represent mean ± SEM of 3 independent experiments.
Figure 5
Figure 5
Confocal microscopy images of the cellular uptake of fluorescein-labelled docetaxel (at a concentration of 12 μg/well) entrapped in transferrin-bearing and control zein-based hybrid lipid nanoparticles as well as in solution, after incubation for 15 h with PC3-Luc (A), DU145 (B), and LNCaP cells (C). Blue: nuclei stained with DAPI (excitation: 405 nm laser line, bandwidth: 400–480 nm), green: fluorescein-labelled docetaxel (excitation: 494 nm laser line, bandwidth: 510–530 nm) (bar size: 20 μm).
Figure 5
Figure 5
Confocal microscopy images of the cellular uptake of fluorescein-labelled docetaxel (at a concentration of 12 μg/well) entrapped in transferrin-bearing and control zein-based hybrid lipid nanoparticles as well as in solution, after incubation for 15 h with PC3-Luc (A), DU145 (B), and LNCaP cells (C). Blue: nuclei stained with DAPI (excitation: 405 nm laser line, bandwidth: 400–480 nm), green: fluorescein-labelled docetaxel (excitation: 494 nm laser line, bandwidth: 510–530 nm) (bar size: 20 μm).
Figure 5
Figure 5
Confocal microscopy images of the cellular uptake of fluorescein-labelled docetaxel (at a concentration of 12 μg/well) entrapped in transferrin-bearing and control zein-based hybrid lipid nanoparticles as well as in solution, after incubation for 15 h with PC3-Luc (A), DU145 (B), and LNCaP cells (C). Blue: nuclei stained with DAPI (excitation: 405 nm laser line, bandwidth: 400–480 nm), green: fluorescein-labelled docetaxel (excitation: 494 nm laser line, bandwidth: 510–530 nm) (bar size: 20 μm).
Figure 6
Figure 6
Relative cellular uptake of fluorescein-labelled docetaxel entrapped in Tf-bearing zein-based hybrid lipid nanoparticles by PC3-Luc cells in the presence of endocytosis inhibitors, using flow cytometry (A) and confocal microscopy (B) (*: p < 0.05 vs. no inhibitor). Results represent mean ± SEM of 3 repeats.
Figure 7
Figure 7
Anti-proliferative efficacy of docetaxel entrapped in Tf-bearing zein-based hybrid lipid nanoparticles (dark grey), control lipid nanoparticles (grey), or in solution (white), on PC3-Luc (A), DU145 (B), and LNCaP (C) cells (*: p < 0.05 vs. the drug concentration leading to the highest cell viability) (n = 15).
Figure 8
Figure 8
DNA condensation to Tf-bearing zein-based hybrid lipid nanoparticles at various polymer–DNA ratios, using PicoGreen® assay (A) (n = 4) and gel retardation assay (B) (error bars smaller than symbols when not visible).
Figure 9
Figure 9
Size (A) and zeta potential (B) of transferrin-bearing zein-based hybrid lipid nanoparticles (black, ■) and control zein-based hybrid lipid nanoparticles (red, ●) complexed with DNA at various polymer–DNA weight ratios. Results are expressed as mean ± SEM (n = 4) (error bars smaller than symbols when not visible).
Figure 10
Figure 10
Gene expression efficacy of transferrin-bearing zein-based hybrid lipid nanoparticles in PC3-Luc (A), DU145 (B), and LNCaP cells (C). Results are expressed as mean ± SEM (n = 15), using DAB–DNA and PEI–DNA as positive controls (*: p < 0.05 vs. the polymer–DNA ratio leading to the highest transfection).
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